Pharmaceutical compositions having desirable bioavailability

ABSTRACT

The present invention is directed to the provision of pharmaceutical compositions. The compositions include a therapeutic agent and a relatively low amount of surfactant for providing higher bioavailability of the therapeutic agent. The compositions are particularly desirable as ophthalmic compositions in which the therapeutic agent is a prostaglandin such as travoprost and the surfactant is a vegetable oil such as castor oil.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 13/442,475(now allowed), filed Apr. 9, 2012, which is a continuation of U.S. Ser.No. 12/403,529 (now U.S. Pat. No. 8,178,582), filed Mar. 13, 2009, whichclaims priority based on U.S. Provisional Patent Application Ser. No.61/037,117 filed Mar. 17, 2008, and U.S. Provisional Patent ApplicationSer. No. 61/111,920, filed Nov. 6, 2008.

TECHNICAL FIELD OF THE INVENTION

The present invention is related to pharmaceutical compositions thatcontain surfactant concentrations that promote bioavailability of atherapeutic agent in the composition. More specifically the presentinvention relates to topical pharmaceutical compositions (e.g.,multi-dose ophthalmic compositions) having relatively low concentrationsof surfactant that promote the bioavailability of a therapeutic agent(e.g., a prostaglandin such as travoprost).

BACKGROUND OF THE INVENTION

The present invention is directed to pharmaceutical compositionsformulated to exhibit enhanced bioavailability of a therapeutic agent ofthe composition. The composition may also exhibit other additional oralternative desired characteristics. For example, the composition mayalso be sterile, may exhibit desired antimicrobial or preservationefficacy, may exhibit a desired degree of stability, combinationsthereof or the like.

Therapeutic agents (e.g., ophthalmic drugs) of many pharmaceuticalcompositions are often required to be stable within those compositions.It is typically undesirable for the therapeutic agents or overallcompositions to decompose or chemically or physically change to asignificant degree prior to application of the agents to an individualor otherwise. For maintaining stability, pharmaceutical compositions aretypically formulated with ingredients that can enhance such stability oringredients that can minimize destabilizing effects of other entities(e.g., chemicals, ambient conditions or the like).

Surfactants are one preferred family of ingredients that have exhibitedsignificant efficacy in stabilizing pharmaceutical compositions and/ortherapeutic agents thereof (particularly aqueous ophthalmic solutionsincluding relatively lipophilic and/or relatively insoluble components).Moreover, it has generally been believed that stability of an agent orcomposition can often be achieved by using larger concentrations ofsurfactant within that pharmaceutical composition.

In addition to stability of the agents or compositions, it is alsotypically desirable for the therapeutic agents of the pharmaceuticalcompositions to exhibit relatively high degrees of bioavailability. Suchbioavailability often becomes particularly important where the method ormanner of application or dosing of a particular pharmaceuticalcomposition provides only a limited amount of time for the therapeuticagent of that composition to be absorbed or otherwise taken in by abiological target such as an eye, ear, throat or nose of an individual.As an example, topically applied ophthalmic pharmaceutical compositionsmay only dwell in or on an individual's eye for a limited period of time(e.g., before tears transport the composition elsewhere). Thus, it isoften desirable to limit the concentration of any ingredient in apharmaceutical composition where that ingredient tends to inhibitbioavailability of a therapeutic agent of that composition.

Recently, it has been discovered that surfactants, when used at certainhigher concentrations, may act as an ingredient that can limit thebioavailability of a therapeutic agent, particularly an ophthalmictherapeutic agent. As a consequence, the addition of surfactant topharmaceutical compositions and particularly ophthalmic compositions canlimit the bioavailability and, in turn, the efficacy of the therapeuticagent in the composition. However, as suggested above, surfactants canalso be quite desirable in a pharmaceutical composition since they cansignificantly enhance the stability of a pharmaceutical composition ortherapeutic agent.

In view of the above, it would be desirable to provide a pharmaceuticalcomposition with a lower surfactant concentration and/or a higherbioavailability of a therapeutic agent. Moreover, it would also bedesirable, although not required unless otherwise specifically stated,for such composition to exhibit a desirable level of stability.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to a pharmaceuticalcomposition, particularly an ophthalmic composition, that combines atherapeutic agent with a relatively low surfactant concentration.Typically, the composition will exhibit a higher bioavailability of thetherapeutic agent particularly when used for topical applications. Inone embodiment, an effectively low amount of surfactant is provided suchthat an area under a concentration/time curve when determined for thepharmaceutical composition of the present invention as applied to abiological target is at least 130%, more typically at least 200% andeven possibly at least 250% relative to an area under a similarconcentration/time curve when determined for a control composition asapplied to the biological target. For such embodiment, the controlcomposition will typically have at least double the amount of surfactantrelative to the pharmaceutical composition.

The present invention has been found particularly suitable for use inophthalmic compositions and more particularly multi-dose ophthalmicsolutions, which tend to be aqueous, but may be otherwise. One exemplarycombination of therapeutic agent and surfactant for such compositions isthe combination of a prostaglandin (e.g., travoprost) with anethoxylated and/or hydrogenated vegetable oil (e.g., Polyoxyl 40Hydrogenated castor oil). In such a combination, the amount ofsurfactant is typically below about 0.4 w/v % of the composition and theamount of therapeutic agent is typically below about 0.01 w/v % of thecomposition.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an exemplary graph of free therapeutic agent relative tosurfactant concentration for an exemplary ophthalmic composition inaccordance with an aspect of the present invention.

FIG. 2 is an exemplary graph of concentration of prostaglandintherapeutic agent at a biological target versus time.

FIG. 3 is an exemplary graph of concentration of prostaglandintherapeutic agent at a biological target versus time in accordance withan aspect of the present invention.

FIG. 4 is an exemplary graph of concentration of prostaglandintherapeutic agent at a biological target versus time in accordance withan aspect of the present invention.

FIG. 5 is an exemplary graph of concentration of therapeutic agent(i.e., carbonic anhydrase inhibitor) at a biological target versus timein accordance with an aspect of the present invention.

FIG. 6 is an exemplary graph of concentration of therapeutic agent(i.e., carbonic anhydrase inhibitor) at a biological target versus timein accordance with an aspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated upon the provision of apharmaceutical composition having a relatively low amount of surfactantand enhanced bioavailability of a therapeutic agent of the composition.The pharmaceutical composition is particularly desirable as a solutionsuitable for topical application to a biological target of the humanbody such as the ear, nose, throat or eye. In a highly preferredembodiment, the pharmaceutical composition is an aqueous or other typeof ophthalmic composition that is provided as a solution. Moreover, itis preferred that the ophthalmic solution have a therapeutic agentsuitable for treatment of one or more eye or ophthalmic maladies such asallergies, glaucoma, dry eye, macular degeneration, cataracts,combinations thereof or the like. As one highly preferred example, atherapeutic agent such as travoprost might be combined in an ophthalmiccomposition with a relatively low amount of surfactant for the treatmentof glaucoma.

Unless otherwise indicated, percentages provided for the ingredients ofthe pharmaceutical composition of the present invention areweight/volume percentages (w/v %).

A combination of surfactant and therapeutic agent can be used accordingto the present invention to enhance the bioavailability of thetherapeutic agent in the pharmaceutical composition. The combination ofsurfactant and therapeutic agent can be useful for variouspharmaceutical compositions such as ophthalmic, otic, nasal anddermatological compositions, but has been found particularly useful forthe ophthalmic compositions. Examples of compositions include:ophthalmic pharmaceutical compositions, such as topical compositionsused in the treatment of glaucoma, infections, allergies orinflammation; compositions for treating contact lenses, such as cleaningproducts and products for enhancing the ocular comfort of patientswearing contact lenses; and various other types of ophthalmiccompositions, such as ocular lubricating products, artificial tears,astringents, and so on. The compositions may be aqueous or non-aqueous,but will often be aqueous. As suggested, the compositions can becompletely aqueous solutions, suspensions or otherwise.

The compositions of the present invention may contain various types oftherapeutic agent. The invention can include therapeutic agents that arenonionic, anionic, cationic or combinations thereof. The therapeuticagent that exhibits higher bioavailability according to the presentinvention will typically be substantially or entirely non-ionic. Thecompositions of the present invention can also include one or moretherapeutic agents where the bioavailability of those agents are notsignificantly affected by surfactant concentrations while thebioavailability of one or more other therapeutic agents are affected.For example, one of the former therapeutic agents could be part of asuspension while one of the latter therapeutic agents may be in thesolution (e.g., dissolved in aqueous solution) of the suspension.

Examples of therapeutic agents that may be contained in the ophthalmicor other compositions of the present invention include timolol (e.g.,timolol maleate), olopatadine (e.g., olopatadine hydrochloride),brinzolamide, tandospirone, roscovitine, nepafenac, combinations thereofor the like. Examples of therapeutic agents that may exhibit increasedbioavailability in accordance with the present invention include,without limitation, hypotensive lipids (e.g., bimatoprost), andglucocorticoids (e.g., prednisolone, dexamethasone and lotoporednol).Therapeutic agents that typically exhibit significant increasedbioavailability in accordance with the present invention areprostaglandins (e.g., latanoprost, travoprost and unoprostone).

As used herein, it is contemplated that the term “prostaglandin”includes, without limitation, natural prostaglandins, prostaglandinanalogs, prostaglandin derivatives or any combination thereof.

The amount of therapeutic agent in the pharmaceutical composition willdepend upon factors such as the efficacy of therapeutic agent atdifferent concentrations, the compatibility of the therapeutic agentwith other ingredients in the composition, the ability of biologicaltarget to accept various amounts of therapeutic agent, combinationsthereof or the like. Generally speaking, the pharmaceutical compositioncan include at least 0.0001% by weight or w/v %, at least 0.001% byweight or w/v % or even at least 0.01% or 0.1% by weight or w/v % ormore of the therapeutic agent. Also, generally speaking, thepharmaceutical composition can include less than 90% by weight or w/v %,less than 40% by weight or w/v % and still more typically less than 10%by weight or w/v % or less of the therapeutic agent.

Therapeutic agent that exhibits a desired degree of improvedbioavailability according to the present invention is typically composedof agent that exhibits relatively low solubility in water. Thus, it iscontemplated that the therapeutic agent of the pharmaceuticalcomposition, particularly when it is employed in an aqueous ophthalmiccomposition, can exhibit solubility in water that is less than 0.1%,more typically less than 0.05%. It is also typically desirable for thetherapeutic agent to be non-ionic, particularly in aqueous solution. Itis also typically desirable for the therapeutic agent to be dissolved insolution of the ophthalmic or pharmaceutical composition which istypically accomplished with the assistance of the surfactant.

Further, therapeutic agent that exhibits a desired degree of improvedbioavailability according to the present invention is typicallylipophilic (i.e., it prefers an organic phase as compared to water or anaqueous phase). Such agent typically has a relatively high octanol/waterpartition coefficient. Thus, it is contemplated that the therapeuticagent of the pharmaceutical composition, particularly when it isemployed in an aqueous ophthalmic composition, can exhibit anoctanol/water partition coefficient that is typically at least 5 andmore typically at least 10.

It is contemplated that the therapeutic agent can be partially orsubstantially entirely of one or more therapeutic agents that have theaforementioned solubility and/or partition component. As used herein,the term “substantially entirely”, when used to describe whatingredient[s] are part of a component of the ophthalmic composition,means that it is contemplated that the component is formed entirely ofone or more particular ingredient[s] or is formed substantially entirelyof those one or more particular ingredient[s] with only a nominal amount(e.g., less than 5% or 1% by weight) of the component being formed ofother than those one or more particular ingredients.

The surfactant included in the pharmaceutical composition of the presentinvention will often depend upon the therapeutic agent in thecomposition or other ingredients of the composition. Preferably, andparticularly for aqueous applications, the surfactant can increase thesolubility of the therapeutic agent and/or at least assist in assuringthat the agent is distributed evenly in the composition. The surfactantmay also promote the ability of the therapeutic agent to penetrate humantissue (e.g., corneal tissue of the eye) thereby further increasing thebioavailability of the agent.

The amount of surfactant will typically depend upon the therapeuticagent employed in the composition. The amount of surfactant employed istypically chosen so as to increase the bioavailability of thetherapeutic agent. Generally speaking, the pharmaceutical compositioncan include at least 0.001% by weight or w/v %, at least 0.01% by weightor w/v %, at least 0.05% by weight or w/v % or even at least 0.5% or1.0% by weight or w/v % or more of the surfactant. Also, generallyspeaking, the pharmaceutical composition can include less than 30% byweight or w/v %, less than 5% by weight or w/v %, still more typicallyless than 2% by weight or w/v % and even possibly less than 0.5% or 0.4%by weight or w/v % of the surfactant.

The surfactant can include non-ionic, an anionic, a cationic, or anamphoteric or zwitterionic surfactant or a combination of suchsurfactants. It is highly preferred that at least a portion orsubstantially the entirety of the surfactant be non-ionic for assistingin providing enhanced bioavailability of the therapeutic agent. As usedherein, the phrase “substantially the entirety of the surfactant” isused to suggest either the entirety of the surfactant or the entirety ofthe surfactant with the exception of a nominal amount of surfactant orboth.

Examples of potentially suitable surfactant include, without limitation,ethers of fatty alcohols and/or polyoxyethylene alkyl ethers, e.g.,macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oilderivatives, polyoxyethylene sorbitan fatty acid esters, e.g., thecommercially available Tweens™, polyoxyethylene stearates, combinationsthereof or the like.

Surfactant that assists in providing for a desired degree ofbioavailability according to the present invention is typically composedof agent that exhibits a relatively high hydrophile/lipophile/balance(HLB). Thus, it is contemplated that the surfactant of thepharmaceutical composition, particularly the ophthalmic composition, hasan HLB value greater than 8, preferably greater than 10 and evenpossibly greater than 12.

The surfactant may include polysorbate 20 (TWEEN 20) (polyoxyethylene 20sorbitan monolaurate), TWEEN 40, TWEEN 60, polysorbate 80 (TWEEN 80),Zwittergent 312, TEEPOL HB7, SPAN 85, pluronic or poloxamers,especially, PLURONIC L62LF, L101, and L64, F68, L44, L121, F-84 andP-103, PEG1000, and/or TETRONIC 1501, 150R1, 701, 901, 1301, and 130R1,poloxamer 333, poloxamer 334, and poloxamer 335, sorbitan oleate,polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholates,sodium deoxytaurocholates, chenodeoxycholic acid, ursodeoxycholic acid,or combinations thereof.

Preferably, the surfactant for the present invention is a non-ionicseed, nut and/or vegetable oil-derived surfactant. Particularlypreferred are seed, nut and/or vegetable oils that have beenhydrogenated, ethoxylated or both. Such surfactants include, but are notlimited, to babassu oil, almond oil, maize oil, palm kernel oil, castoroil, coconut oil, cotton seed oil, jojoba oil, linseed oil, mustard oil,olive oil, peanut oil, safflower oil sesame oil, soybean oil,sunflower-seed oil and wheat germ oil, their hydrogenated or ethoxylatedderivatives or combinations thereof. Preferred oils are castor oil,babassu oil, almond oil, maize oil and palm kernel oil, most preferablycastor oil and cababassu oil.

Particularly preferred surfactants include Polyoxyethylene (POE) (40)Hydrogenated castor oil (or PEG (40 Hydrogenated castor oil) (HCO-40),POE (60) Hydrogenated castor oil (HCO-60), and POE (200) Hydrogenatedcastor oil (HCO-200).

Without being bound by theory, it is believed that use of higher amountsor concentrations of surfactant relative to the therapeutic agent canresults in higher amounts of the therapeutic agent being absorbed intothe micelle of the surfactants as the therapeutic agent is solubilized.In turn, it is believed that such absorption can limit the amount oftherapeutic agent readily available to a biological target (e.g., thecornea of a human eye) during topical application of the pharmaceuticalcomposition (e.g., topical application of an ophthalmic solution). Itshould be understood that this theory is not binding upon the scope ofthe present invention unless otherwise specifically recited.

It is contemplated that the pharmaceutical composition of the presentinvention can include an effectively low amount of surfactant such thatthe concentration of the therapeutic agent located at a biologicaltarget is substantially greater than the concentration of therapeuticagent located at the same biological target after a separate applicationof a control composition. As used herein, a “separate application of acontrol composition” is an application of the control composition to asame biologic target of a separate animal. For example, testing can beperformed on two sets of ten rabbits apiece wherein the composition ofthe present invention is applied to an eye of each rabbit of the firstset while the control composition is applied to an eye of each rabbit ofthe second set. In such embodiment, the control composition issubstantially identical to the pharmaceutical composition with theexception that the concentration of surfactant is at least doubled, morepreferably tripled and even more typically quadrupled in the controlcomposition relative to the pharmaceutical composition of the presentinvention. Moreover, the pharmaceutical composition of the presentinvention is applied in an amount that is equivalent to the amount ofcontrol composition applied.

For quantifying such concentrations, a graph is developed, an example ofwhich is shown in FIG. 2, plotting concentration at the biologicaltarget relative to time after application of the pharmaceuticalcomposition. The concentration is determined at three separate times atthe biological target. In particular, the concentration is determined at1 hour, 2 hours and 4 hours after application. These points are thenplotted on the graph. Examples of such points 10, 12, 14 are shown inFIG. 2. Those points are then connected by line segments and the area 16under those line segments (referred to herein as area under theconcentration/time curve) is determined as a quantification ofconcentration. Using this area under the curve measurement, it has beendetermined that the area under the concentration/time curve whendetermined for the pharmaceutical composition of the present inventionas applied to the biological target is at least 130%, more typically atleast 150% and even possibly at least 200% relative to the area underthe concentration/time curve when determined for the control compositionas applied to the biological target. One preferred protocol forapplication of control composition and pharmaceutical composition aswell as measurement of concentration of therapeutic agent is provided inthe example section below.

As an example of area under the curve measurements, an exemplarysituation is provided wherein the concentrations at 1, 2 and 4 hours forthe composition of the present invention is 20 nanograms per milliliter(ng/ml) and the concentrations at 1, 2 and 4 hours for the controlcomposition are 10 ng/ml. In such a situation the area under the curvefor the composition of the present invention is 20 ng/ml×3 hr, which is60 while the area under curve for the control composition is 10 ng/ml×3hr, which is 30. In this scenario, the area under the curve for thecomposition of the present invention is 200% that of the area under thecurve for the composition of the control composition.

It has been found that the bioavailability of certain therapeutic agentsis sensitive to the amount of surfactant employed in conjunction withthose therapeutic agents. This is particularly true when thepharmaceutical composition of the present invention is an ophthalmiccomposition such as a single-dose or multi-dose aqueous ophthalmiccomposition. As a class, it is believed that the therapeutic agentclassified herein as prostaglandins exhibit a higher degree ofbioavailability when employed in conjunction with relatively lowconcentrations of surfactants classified herein as vegetable, nut orseed oil surfactants, particularly vegetable oil surfactants. It hasbeen discovered that travoprost in particular exhibits a higher degreeof bioavailability in an aqueous ophthalmic composition of the presentinvention when used in conjunction with a relatively low concentrationof an ethoxylated and/or hydrogenated vegetable oil surfactant such asPolyoxyethylene (POE) (40) Hydrogenated castor oil (or PEG (40Hydrogenated castor oil) (HCO-40), POE (60) Hydrogenated castor oil(HCO-60), and POE (200) Hydrogenated castor oil (HCO-200), combinationsthereof or the like. As such, it is contemplated that the surfactant ofthe present invention can be entirely or substantially entirely one ormore ethoxylated and/or hydrogenated vegetable oils such asPolyoxyethylene (POE) (40) Hydrogenated castor oil (or PEG (40Hydrogenated castor oil) (HCO-40), POE (60) Hydrogenated castor oil(HCO-60), and POE (200) Hydrogenated castor oil (HCO-200), combinationsthereof or the like and the therapeutic agent can be entirely orsubstantially entirely one or more prostaglandins such as latanoprost,travoprost, unoprostone or combinations thereof.

In such an aqueous ophthalmic composition having prostaglandintherapeutic agent (e.g., travoprost) and hydrogenated and/or ethoxylatedvegetable oil surfactant (e.g., HCO-40), the amount of such therapeuticagent is typically at least 0.00001 w/v %, at least 0.0001% w/v % oreven at least 0.001 w/v % of the composition. Moreover, such compositiontypically includes less than 5 w/v %, more typically less than 0.05% w/v% and still more typically less than 0.01 w/v % such therapeutic agent.Further, the composition typically includes at least 0.005 w/v %, atleast 0.01 w/v % or even at least 0.03 w/v % such surfactant. Thecomposition also typically includes less than 0.5 w/v %, more typicallyless than 0.4 w/v %, even more typically less than 0.3 w/v % and evenpossibly less than 0.15 w/v % such surfactant.

It is contemplated that area under the concentration/time curvemeasurements as described above can specifically be performed for suchprostaglandin/surfactant combinations. The ophthalmic composition havingprostaglandin therapeutic agent and hydrogenated and/or ethoxylatedvegetable oil surfactant preferably includes an effectively low amountof surfactant such that the area under the concentration/time curve whendetermined for the ophthalmic composition of the present invention asfor the aqueous humor of an eye is at least 130%, more typically atleast 150% and even possibly at least 200% relative to the area underthe concentration/time curve when determined for the control compositionas for the aqueous humor of an eye. In such embodiment, the controlcomposition is substantially identical to the pharmaceutical compositionwith the exception that the concentration of surfactant is at leastdoubled, more preferably tripled and even more typically quadrupled inthe control composition relative to the ophthalmic composition of thepresent invention. Moreover, the ophthalmic composition of the presentinvention is applied in an amount that is equivalent to the amount ofcontrol composition applied. It is further contemplated that suchconcentrations can be similarly taken for the iris-ciliary body.

As suggested previously, concentrations for the composition of thepresent invention and the control composition can be carried out, for atleast one embodiment of the present invention, according to the testingprotocol provided below.

The pharmaceutical compositions of the present invention, particularlywhen they are ophthalmic compositions, will generally be formulated assterile aqueous solutions. These compositions are also formulated so asto be compatible with the eye and/or other tissues to be treated withthe compositions. The ophthalmic compositions intended for directapplication to the eye will typically be formulated so as to have a pHand tonicity that are compatible with the eye. It is also contemplatedthat the compositions can be suspensions or other types of solutions.The ophthalmic compositions will typically have a pH in the range of 4to 9, preferably 5.5 to 8.5, and most preferably 5.5 to 8.0.Particularly desired pH ranges are 6.0 to 7.8 and more specifically 6.4to 7.2 or 7.5.

The pharmaceutical compositions, particularly ophthalmic compositions,of the present invention can include a polymer or a viscosity agent thatfurther enhances bioavailability by extending the retention time of thecompositions in or on the tear film of the eye, the cull-de-sac of theeye or elsewhere on the eye or another biological target. The preferredpolymers include, without limitation, hydroxyethyl cellulose,hydroxypropylmethyl cellulose, carbomer, carbopol, xanthan gum, anycombination thereof or the like.

In one embodiment, the pharmaceutical composition of the presentinvention is an ophthalmic aqueous solution or other similar solution.Such a solution will typically include a preservative system. As usedherein, a “preservative system” is one or a group of ingredientsincluded within the ophthalmic solution for maintaining antimicrobialactivity in the solution. A solution may be a self-preserving solutionif its ingredients naturally provide for anti-microbial activity andsuch solution still includes a preservative system. Examples ofophthalmic solutions or ingredients suitable for such solutions wherethose solutions may benefit from the teaching of the present inventionare disclosed in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791;4,525,346; 4,836,986; 5,037,647; 5,300,287; 5,817,277; 6,503,497;5,741,817; 6,319,464; 6,348,190; 6,348,190; 6,482,799; 5,320,843;5,221,664; 6,034,043; 4,522,806; 6,017,861 and U.S. Patent Publications:2002/0122831; and PCT application WO 91/09523 (Dziabo et al.); and JP2003-104870, all of which are incorporated herein by reference for allpurposes. One particular Ophthalmic Solution which may benefit from theteachings of the present invention is disclosed in U.S. PatentPublication No. 2009/0232763, filed Mar. 3, 2009, titled “AqueousPharmaceutical Compositions Containing Borate-Polyol Complexes”,incorporated herein by reference for all purposes.

Accordingly, the preservative system of the pharmaceutical compositionof the present invention can include a borate. As used herein, the term“borate” shall refer to boric acid, salts of boric acid and otherpharmaceutically acceptable borates, or combinations thereof. Mostsuitable are: boric acid, sodium borate, potassium borate, calciumborate, magnesium borate, manganese borate, and other such borate salts.Borate interacts with polyols, such as glycerol, propylene glycol,sorbitol and mannitol, to form borate polyol complexes. The type andratio of such complexes depends on the number of OH groups of a polyolon adjacent carbon atoms that are not in trans configuration relative toeach other. It shall be understood that weight/volume percentages of theingredients polyol and borate include those amounts whether as part of acomplex or not.

When used, borate is generally used in the composition of the presentinvention in an amount that is greater than about 0.001 w/v %, moretypically greater than about 0.01 w/v % and even more typically greaterthan about 0.07% w/v % of the pharmaceutical composition. Moreover, whenused, the borate is generally used in the compositions of the presentinvention in an amount that is less than about 5 w/v %, more typicallyless than about 1.2 w/v % and even more typically less than about 0.8w/v % of the pharmaceutical composition.

The preservative system of the pharmaceutical composition may alsoinclude one or more polyols. As used herein, the term “polyol” includesany compound having at least one hydroxyl group on each of two adjacentcarbon atoms that are not in trans configuration relative to each other.The polyols can be linear or cyclic, substituted or unsubstituted, ormixtures thereof, so long as the resultant complex is water soluble andpharmaceutically acceptable. Examples of such compounds include: sugars,sugar alcohols, sugar acids and uronic acids. Preferred polyols aresugars, sugar alcohols and sugar acids, including, but not limited to:mannitol, glycerin, xylitol, sorbitol and propylene glycol.

When used, polyol generally used in the composition of the presentinvention in an amount that is greater than about 0.001 w/v %, moretypically greater than about 0.01 w/v % and even more typically greaterthan about 0.07 w/v % of the pharmaceutical composition. Moreover, whenused, polyol is generally used in the compositions of the presentinvention in an amount that is less than about 5 w/v %, more typicallyless than about 1.2 w/v % and even more typically less than about 0.8w/v % of the pharmaceutical composition.

The compositions of the present invention can include a preservative.Potential preservatives include, without limitation, hydrogen peroxide,chlorine containing preservatives such as benzalkonium chloride orothers. According to a preferred aspect, however, the ophthalmiccomposition of the present invention is substantially free of anychloride containing preservatives and, particularly, is substantiallyfree of benzalkonium chloride. Highly preferred preservatives includedfor ophthalmic uses are polymeric quaternary ammonium compounds. It isnoted that use of the amounts of surfactant specified herein canincrease bioavailability in a manner that can at least partially orsubstantially entirely offset losses in bioavailability that may occurwhen benzalkonium chloride or other such ingredient are not present.

As used herein, the phrase “substantially free of” as it refers to aningredient of the ophthalmic composition means that the ophthalmicsolution is either entirely devoid of that particular ingredient orincludes only a nominal amount of that particular ingredient.

The polymeric quaternary ammonium compounds useful in the compositionsof the present invention are those which have an antimicrobial effectand which are ophthalmically acceptable. Preferred compounds of thistype are described in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791;4,525,346; 4,836,986; 5,037,647 and 5,300,287; and PCT application WO91/09523 (Dziabo et al.). The most preferred polymeric ammonium compoundis polyquaternium 1, otherwise known as POLYQUAD® or ONAMERM® with anumber average molecular weight between 2,000 to 30,000. Preferably, thenumber average molecular weight is between 3,000 to 14,000.

When used, the polymeric quaternary ammonium compounds or otherpreservatives are generally used in the compositions of the presentinvention in an amount that is greater than about 0.00001 w/v %, moretypically greater than about 0.0003 w/v % and even more typicallygreater than about 0.0007 w/v % of the pharmaceutical composition.Moreover, when used, the polymeric quaternary ammonium compounds orother preservatives are generally used in the compositions of thepresent invention in an amount that is less than about 3 w/v %, moretypically less than about 0.003 w/v % and even more typically less thanabout 0.0015 w/v % of the pharmaceutical composition.

The pharmaceutical compositions of the present invention can be amulti-dose ophthalmic compositions having sufficient antimicrobialactivity to allow the composition to satisfy the USP preservativeefficacy requirements, as well as other preservative efficacy standardsfor aqueous pharmaceutical compositions.

The preservative efficacy standards for multi-dose ophthalmic solutionsin the U.S. and other countries/regions are set forth in the followingtable:

Preservative Efficacy Test (“PET”) Criteria (Log Order Reduction ofMicrobial Inoculum Over Time Bacteria Fungi USP 27 A reduction of 1 log(90%), The compositions must demonstrate over the by day 7; 3 logs(99.9%) by entire test period, which means no increases of day 14; andno increase after 0.5 logs or greater, relative to the initial inoculumday 14 Japan 3 logs by 14 days; and no No increase from initial count at14 and 28 days increase from day 14 through day 28 Ph. Eur. A¹ Areduction of 2 logs (99%) A reduction of 2 logs (99%) by 7 days, and noby 6 hours; 3 logs by 24 increase thereafter hours; and no recoveryafter 28 days Ph. Eur. B A reduction of 1 log at 24 A reduction of 1 log(90%) by day 14, and no hours; 3 logs by day 7; and no increasethereafter increase thereafter FDA/ISO A reduction of 3 logs from Noincrease higher than the initial value at day 14, 14730 initialchallenge at day 14; and no increase higher than the day 14 and areduction of 3 logs from rechallenge count through day 28 rechallenge¹There are two preservative efficacy standards in the EuropeanPharmacopoeia ‘“A” and “B”.

The standards identified above for the USP 27 are substantiallyidentical to the requirements set forth in prior editions of the USP,particularly USP 24, USP 25 and USP 26.

Table A below provides a listing of exemplary ingredients suitable foran exemplary preferred formulation of the ophthalmic composition of thepresent invention and a desired percentage for those ingredients.

TABLE A Ingredient w/v Percent Travoprost 0.004 Polyoxyl 40 HydrogenatedCastor Oil ≦0.2 or ≧0.05 (HCO-40) Boric Acid 0.3 Zinc Chloride 0.0025Sorbitol 0.25 Propylene Glycol 1.6 Sodium Chloride 0.35 NaOH sufficientto achieve pH = 6.8 purified water Q.S. 100

It is understood that the weight/volume percents in table A can bevaried by ±10%, ±20%, ±30%, ±90% of those weight/volume percents or moreand that those variances can be specifically used to create ranges forthe ingredients of the present invention. For example, an ingredientweight/volume percent of 10% with a variance of ±20% means that theingredient can have a weight/volume percentage range of 8% to 12 w/v %.

With reference to FIG. 1, experiments were performed for severalpharmaceutical compositions varying the amount of surfactant in thosecompositions. In particular, the amount or percentage of free oravailable travoprost was determined for compositions having the sameingredients as the compositions of table E with the exception thatsurfactant level were varied. As can be seen, the concentration ofsurfactant can have a significant effect upon the availability of thetravoprost.

Notably, these preservative systems can at least assist in providingstability to the compositions of the present invention. Such systemscan, in many instances, offset stability that may be lost through theuse of less surfactant.

Applicants specifically incorporate the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the invention be limited to the specificvalues recited when defining a range.

As suggested above, the relatively low concentrations of surfactant canbe employed in formulations having multiple different therapeutic agentsfor producing desired bioavailability of those agents. Additionally,however, it has been found, that composition with particularcombinations of therapeutic (combination compositions) agents gainsignificant benefits from the surfactant of the present invention,particularly when it is used at lower concentrations, but alsopotentially when it is used at higher concentrations.

In particular, it has been found that the surfactant that, when used atlow concentrations, assists in solubilizing and/or increasesbioavailability of the particular therapeutic agents discussed herein(e.g., prostaglandins such as travoprost) and can also act as a wettingagent for other therapeutic agents such a carbonic anhydrase inhibitorssuch as brinzolamide. Thus, the surfactant can provide a dual functionwithin the composition (e.g., ophthalmic aqueous composition). This dualfunction can then allow the composition to include only a singlesurfactant. Of course, multiple surfactants may be employed unlessotherwise specifically stated.

It is contemplated that any of the preferred surfactants discussedherein as being capable of enhancing the bioavailability of atherapeutic agent and/or having the properties that provide suchcapability may used to perform this dual function. Thus, a preferredsurfactant for combination composition, like the preferred surfactantfor the rest of the compositions herein, is a non-ionic seed, nut and/orvegetable oil-derived surfactant. Particularly preferred are seed, nutand/or vegetable oils that have been hydrogenated, ethoxylated or both.Such surfactants include, but are not limited, to babassu oil, almondoil, maize oil, palm kernel oil, castor oil, coconut oil, cotton seedoil, jojoba oil, linseed oil, mustard oil, olive oil, peanut oil,safflower oil sesame oil, soybean oil, sunflower-seed oil and wheat germoil, their hydrogenated or ethoxylated derivatives or combinationsthereof. Preferred oils are castor oil, babassu oil, almond oil, maizeoil and palm kernel oil, most preferably castor oil and cababassu oil.

Particularly preferred surfactants include Polyoxyethylene (POE) (40)Hydrogenated castor oil (or PEG (40 Hydrogenated castor oil) (HCO-40),POE (60) Hydrogenated castor oil (HCO-60), and POE (200) Hydrogenatedcastor oil (HCO-200).

Where higher bioavailability is desired, the surfactant for thecombination composition can be used at the low concentrations that havealready been disclosed herein. However, it is also contemplated thathigher concentrations of such surfactant may be employed incircumstances where bioavailability is of less concern.

The combination composition benefits from particular advantages when itis formulated as a suspension. The use of the surfactant as discussedfor the combination composition can allow for substantially complete(i.e., at least 80 or 90%) or complete solubilization of one therapeuticagent (e.g., a prostaglandin such as travoprost). At the same time, thesurfactant can provide wetting and/or stabilization to the othertherapeutic agent (e.g., a carbonic anhydrase inhibitor such asbrinzolamide) which is suspended within the suspension. When thesurfactant is used at the low concentrations discussed herein, it canalso significantly improve the bioavailability of the non-suspendedagent. Further, the preferred surfactant can often prevent thesolubilized therapeutic agent from binding to container walls as wouldbe seen if other surfactants were employed.

It is to be understood that any of the excipients discussed herein canbe used in these combination compositions whether the compositions aresuspensions, other aqueous solutions or other compositions. Moreover,the skilled artisan will understand that the discussions of thetherapeutic agents and surfactants, when discussing any of thecompositions herein, also applies to the combination compositions.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

COMPARATIVE EXAMPLES

Table B below provides two compositions, which include a preferredophthalmic composition of the present invention as well as a controlcomposition. The control composition has a surfactant level higher thanthe preferred composition according to the parameters discussed above.

TABLE B INGREDIENTS CONTROL PREFERRED COMPOSITION Travoprost 0.004 0.004Polyoxyethylene 40 0.5 0.1 Hydrogenated Castor Oil (HCO-40) Boric Acid0.3 0.3 Zinc Chloride 0.0025 0.0025 Sorbitol 0.25 0.25 Propylene Glycol1.6 1.6 Sodium Hydroxide Adjust pH 6.0 Adjust pH 6.0 and/or HydrochloricAcid Purified Water QS 100 w/v % QS 100 w/v %

The amount of surfactant (i.e., HCO-40) in the control composition is 5times the amount of surfactant in the preferred composition. Thepreferred composition was applied to the eyes of a first set of rabbitsand then a separate application of the control composition was appliedto the eyes of a second set of rabbits. After application of thepreferred composition and after application of the control composition,concentrations in nanograms per milliliter (ng/mL) of therapeutic agent(i.e., travoprost free acid) were determined for the Aqueous Humor andthe Iris Ciliary of the eyes at various times. The results arerespectively shown below in TABLE C and TABLE D.

TABLE C Standard Preferred Standard Time Control Deviation CompositionDeviation 0.25 1.13 0.37 2.01 0.87 0.5 3.82 1.31 9.17 2.72 1 6.87 2.4020.78 4.35 2 5.90 1.17 18.40 6.08 4 5.05 2.78 10.24 3.69 6 0.57 0.151.20 0.77

TABLE D Standard Preferred Standard Time Control Deviation CompositionDeviation 0.25 1.40 0.29 1.71 0.42 0.5 2.43 0.94 5.86 1.88 1 3.33 0.769.32 2.68 2 2.79 0.39 7.59 3.25 4 1.98 1.14 4.69 1.59 6 BLQ — 0.75 0.26

As can be seen from Tables B through D, the amount of therapeutic agentin the tested portion of the eyes was substantially higher in thepreferred composition relative to the control composition.

Table E below shows further preferred compositions A, B and C of thepresent invention. After application of these preferred compositions inthe eyes of rabbits, concentrations (in nanograms per milliliter (ng/mL)of therapeutic agent (i.e., travoprost free acid) were determined forthe Aqueous Humor of the eyes at various times.

TABLE E Ingredients Composition A Composition B Composition C Travoprost0.004 0.004 0.002 Polyoxyethylene 40 0.1 0.03 0.1 Hydrogenated CastorOil (HCO-40) Boric Acid 0.3 0.3 0.3 Mannitol 0.3 0.3 0.3 PropyleneGlycol 0.75 0.75 0.75 Sodium chloride 0.35 0.35 0.35 Polyquaternium-10.001 0.001 0.001 Hydrochloric Acid Adj pH to 6.8 Adj pH to 6.8 Adj pHto 6.8 and/or Sodium HCl Purified Water QS to 100% QS to 100% QS to 100%

Table F below shows the concentrations in nanograms per milliliter(ng/mL) of the therapeutic agent of compositions A, B and C in theAqueous humor of eyes of rabbits at various times after the applicationof the compositions.

TABLE F Sampling Time (n) Composition A Composition B Composition C  60minutes 22.79 ± 7.62 25.64 ± 9.34 13.21 ± 7.79  (9-10) 120 minutes 15.46± 6.73 23.86 ± 4.67 9.23 ± 4.02 (10) 240 minutes  4.73 ± 1.23 12.68 ±9.81 2.59 ± 1.46 (10)

As can be seen, concentrations of the therapeutic agent fromCompositions A through C in the Aqueous humor of the rabbits aredesirably high.

Table G below shows a further preferred composition D of the presentinvention.

TABLE G INGREDIENT COMPOSITION D Travoprost 0.004 Timolol Maleate 0.68Polyoxyl 40 Hydrogenated 0.1 Castor Oil (HCO-40) Boric Acid 0.3 Mannitol0.3 Propylene Glycol 0.75 Sodium Chloride 0.25 Polyquaternium-1 0.001Sodium Hydroxide Adj. pH 6.8 Hydrochloric Acid Adj. pH 6.8 PurifiedWater QS 100%

As discussed above, the amount of surfactant can affect the stability ofthe compositions. Table H shows results of stability testing ofcomposition B through E relative to Composition A, which has a highersurfactant concentration. All formulations A through E were formulatedlike the compositions of table E and contained 0.3% boric acid, 0.3%mannitol, 0.001% Polyquaternium-1 and were adjusted to pH 6.8 withsodium hydroxide and or hydrochloric acid. Composition A and compositioneach contained 0.66% sodium chloride while compositions C through Dincluded 0.75% propylene glycol and 0.35% sodium chloride instead.

Each of the compositions A-E was packaged utilizing a syndiotacticpolypropylene container, polypropylene plug and a polypropylene cap.They were stored at a stress condition of 55° C. for 8 weeks. Controlsamples were stored in a refrigerator at 4° C. These samples wereanalyzed for travoprost assay and the travoprost degradation product(travoprost free acid). The results are provided in Table. Theformulations loose about 6 to 8% moisture upon 8 weeks storage at 55° C.As a result they show increase in travoprost assay at 8 weeks 55° C.

TABLE H Travoprost Travoprost Travoprost free acid Travoprost TravoprostHC0-40 Assay Assay at 8 Assay free acid Concentration Concentration at4C Wks/55C at 4C (% of (% of w/v % w/v % (% Label) (% Label) Travoprost)Travoprost) A 0.004 0.5 96 102 0.0 0.7 96 101 0.0 0.7 B 0.004 0.1 99 1040.0 2.4 99 103 0.0 2.4 C 0.004 0.1 97 101 NT 2.7 97 102 2.7 D 0.004 0.0593 100 0.3 3.1 95 100 0.3 3.1 E 0.004 0.03 91 93 0.0 3.4 92 96 0.0 3.4

As can be seen, the amount of the degradation product increases withdecreasing HCO-40 concentration. However, such increase is relativelyinsignificant for the overall compositions since the amount ofdegradation product is still quite small compare to the total amount oftravoprost that remains in solution.

Bioavailability Examples

Polyoxyl hydrogenated castor oil 40 (HCO-40) is a surfactant thatsolubilizes travoprost and incorporates travoprost into its micelles.HCO-40 can be obtained by reacting 40 to 45 moles of ethylene oxide with1 mole of hydrogenated castor oil. Thus, it typically has a high enoughmolecular weight such that it will not be filtered through a 3000molecular weight cut off filter. An estimate of free fraction oftravoprost, (i.e., fraction travoprost outside the HCO-40 micelle), canbe obtained by filtering the solution through a 3000 molecular weightcut off filter.

The following procedure was used to determine the free fraction oftravoprost. About 2 ml of formulation was placed in a centrifuge tubefitted with a 3000 Molecular weight cut off regenerated cellulosefilter. The sample was centrifuged for approximately 90 minutes at 2000r.p.m. to pass approximately 1 to 1.2 mL of formulation through thefilter. The filtrate and retentate were then collected and assayed fortravoprost using a HPLC procedure. The results are provided in Table Ibelow. Note that the compositions 1 through 15 are all formulated likethose in Table E and each composition contains 0.3% boric acid, 0.3%mannitol, 0.001% Polyquaternium-1 and were adjusted to pH 6.8 withsodium hydroxide and/or hydrochloric acid.

The assay values of filtrate represent the free fraction of travoprost.The results show that free fraction of travoprost increases withdecreasing HCO-40 concentration. It is desired to have free fraction oftravoprost greater than 1%, preferably greater than 2% and mostpreferably greater than 4%. The topical ocular bioavailability isexpected to increase with increasing travoprost concentration and freefraction of travoprost.

TABLE I Travoprost Travoprost Assay of Assay of Weight Weight TravoprostHCO-40 Filtrate, Retentate, of of # Other Excipients ConcentrationConcentration % Label % Label Filtrate Retentate 1 0.66% NaCl 0.004 0.50.8 176 1.00 1.00 2 0.66% NaCl 0.004 0.25 1.7 188 1.01 0.99 3 0.66% NaCl0.004 0.25 1.6 210 1.12 0.86 4 0.66% NaCl 0.002 0.1 3.6 222 1.19 0.80 50.75% propylene 0.002 0.1 3.7 199 1.11 0.89 glycol, 0.35% NaCl 6 0.75%propylene 0.004 0.1 5.2 226 1.18 0.81 glycol, 0.35% NaCl 7 0.75%propylene 0.004 0.1 4.8 197 1.00 0.99 glycol, 0.35% NaCl 8 0.75%propylene 0.004 0.1 5.0 205 1.13 0.88 glycol, 0.35% NaCl 9 0.66% NaCl0.004 0.1 4.4 216 1.13 0.87 10 0.75% propylene 0.001 0.05 8.7 187 1.030.99 glycol, 0.35% NaCl 11 0.75% propylene 0.002 0.05 9.0 214 1.18 0.81glycol, 0.35% NaCl 12 0.75% propylene 0.004 0.05 9.8 196 1.14 0.85glycol, 0.35% NaCl 13 0.75% propylene 0.004 0.05 12.5 217 1.25 0.76glycol, 0.35% NaCl 14 0.75% propylene 0.001 0.03 13.1 219 1.28 0.73glycol, 0.35% NaCl 15 0.75% propylene 0.004 0.03 15.6 166 1.15 0.86glycol, 0.35% NaCl 16 0.75% propylene 0.004 0.03 15.4 201 1.26 0.75glycol, 0.35% NaCl

Thus, in general for the present invention, half (1 ml) of a volumetricamount (2 ml) of composition of the present invention is forced througha molecular weight cut-off filter to form half of the composition into afiltrate and half into a retentate. For such composition, it istypically desirable for the concentration of surfactant in thecomposition to be such that the concentration of therapeutic agent isrelatively high in the filtrate. This can be quantified as afiltrate/retentate ratio, which is equal to the weight/volumeconcentration of therapeutic agent in the filtrate divided by theweight/volume concentration of therapeutic agent in the retentate. Thisratio for the present invention is determined when half (1 ml) of anamount (2 ml) of composition of the present invention is forced througha molecular weight cut-off filter to form a filtrate and a retentatewhere the molecular weight cut-off filter does not allow any or anysubstantial portion of the surfactant to flow through the weight cut-offfilter. For the present invention, this ratio is typically greater than0.0060, more typically greater than 0.014 and even possibly greater than0.035.

Concentration Testing Protocol

The following protocol is at least one method of determiningconcentration of therapeutic agent at a biologic target. New Zealandwhite rabbits each receive a single 30 μA topical ocular dose to eacheye. Aqueous humor samples are collected immediately after euthanasia atthe time points provided in results Table C. The concentration oftravoprost free acid is then determined using tandem mass spectrometry(LC-MS/MS) analysis. Travoprost free acid is extracted from the aqueoushumor samples and reconstituted in a water ethanol mixture. LC-MS-MSanalysis for the determination of travoprost free acid concentrations iscarried out using a Perkin Elmer Sciex AP 3, atmospheric pressureionization mass spectrometer with an electrospray inlet and turbo ionspray, in the negative ion mode. Phenomenex ODS C18 (2) HPLC column isused. 5 mM ammonium formate buffer pH 6.3:methanol (30:70) is used asmobile phase.

Combination Composition Examples

Table J below provides two exemplary preferred formulations(formulations R and S) of combination compositions, which are aqueoussuspensions. The suspensions include two therapeutic agents, thecarbonic anhydrase inhibitor brinzolamide and the prostaglandintravoprost. The compositions also include low concentrations of anexemplary preferred surfactant, HCO-40.

TABLE J Composition W/V Composition R Composition S Brinzolamide 1.0 g1.0 g Travoprost 0.0015 g 0.004 g HCO-40 0.2 g 0.2 g Carbomer 974 P 0.4g 0.4 g Mannitol 3.5 g 2.6 g Edetate disodium 0.01 g 0.01 g BenzalkoniumChloride 0.01 g 0.015 g Sodium chloride 0.18 g 0.35 g NaOH/HCl q.s. to6.5 q.s. to 6.5 Purified water q.s. 100 ml q.s. 100 ml

For purposes of comparison, table K below provides two formulations(formulations T and U) of combination compositions, which are alsoaqueous suspensions. The suspensions include two therapeutic agents, thecarbonic anhydrase inhibitor brinzolamide and the prostaglandintravoprost. The compositions also include relatively higherconcentrations of the surfactant HCO-40 and include tyloxapol as anadditional surfactant.

TABLE K Composition W/V Composition T Composition U Brinzolamide 1.0 g +3% excess 1.0 g + 3% excess Tyloxapol 0.025 g 0.025 g Travoprost 0.0015g 0.004 g HCO-40 0.5 g 0.5 g Carbomer 974 P 0.4 g 0.4 g Povidone K29-320.2 g 0.2 g Mannitol 3.5 g 2.6 g Edetate disodium 0.01 g 0.01 gBenzalkonium Chloride 0.01 g 0.015 g Sodium chloride 0.18 g 0.35 gNaOH/HCl q.s. to 6.5 q.s. to 6.5 Purified water q.s. 100 ml q.s. 100 ml

With reference to FIG. 3, it can be seen that the concentration oftravoprost in the aqueous humor of rabbits was significantly greater forcomposition R than it was for composition T or for a composition thatincludes a same or similar level of a single therapeutic agenttravoprost in combination with HCO-40 at a concentration of 0.5 w/v %.With reference to FIG. 4, it can be seen that the concentration oftravoprost in the aqueous humor of rabbits was significantly greater forcomposition S than it was for composition U or the composition thatincludes a same or similar level of a single therapeutic agent(travoprost) in combination with HCO-40 at a concentration 0.5 w/v %.With reference to FIG. 5, it can be seen that the concentrations ofbrinzolamide in the aqueous humor of rabbits showed a difference that isconsidered small for composition R than it showed for composition T or acomposition that includes a same or similar level of a singletherapeutic agent brinzolamide in combination with HCO-40 at aconcentration of 0.5 w/v %. With reference to FIG. 6, it can be seenthat the concentrations of brinzolamide in the aqueous humor of rabbitsshowed a difference that is considered small for composition S than itshowed for composition U or a composition that includes a same orsimilar level of a single therapeutic agent brinzolamide in combinationwith HCO-40 at a concentration of 0.5 w/v %.

I claim:
 1. An ophthalmic pharmaceutical composition, comprising: apharmaceutical vehicle suitable for topical application to an eye of ahuman; at least 0.001 w/v % but less than 0.01 w/v % travoprost as atherapeutic agent for lowering intraocular pressure; greater than 0.0003w/v % but less than 0.003 w/v % polymeric quaternary ammonium compoundas a preservative; and an effectively low amount of surfactantsufficient for providing a high degree of bioavailability of thetravoprost, wherein: i. the amount of surfactant is at least 0.01 w/v %but below 0.4 w/v % of the composition; ii. the surfactant is entirelyethoxylated and hydrogenated castor oil; iii. the composition issubstantially free of benzalkonium chloride; and iv. the pharmaceuticalvehicle includes water.
 2. A composition as in claim 1 wherein theconcentration of the surfactant is at least 0.03 w/v % but less than 0.3w/v %.
 3. A composition as in claim 1 wherein the composition has a pHof 6.4 to 7.5.
 4. A composition as in claim 1 wherein the surfactant isnon-ionic.
 5. A composition as in claim 1 wherein the composition has apH of 6.4 to 7.2.
 6. A composition as in claim 1 wherein the compositionsatisfies Ph. Eur. A, Ph. Eur. B or both.
 7. A composition as in claim 1wherein the composition is disposed in an eye dropper.
 8. A compositionas in claim 1 wherein concentration of the surfactant in the compositionis less than 0.15 w/v %.
 9. A composition as in claim 1 wherein thesurfactant is entirely Polyoxyl 40 Hydrogenated castor Oil.
 10. Acomposition as in claim 1 wherein the travoprost is in the compositionat a concentration of less than 0.006 w/v %.
 11. A composition as inclaim 1 wherein concentration of the polymeric quaternary ammoniumcompound in the composition is greater than 0.0007 w/v % but less than0.0015 w/v % of the pharmaceutical composition.
 12. A composition as inclaim 1 wherein the polymeric quaternary ammonium compound ispolyquaternium-1.
 13. A composition as in claim 2 wherein thecomposition has a pH of 6.4 to 7.5.
 14. A composition as in claim 13wherein the travoprost is in the composition at a concentration of lessthan 0.006 w/v %.
 15. A composition as in claim 14 wherein thesurfactant is entirely Polyoxyl 40 Hydrogenated castor Oil.
 16. Acomposition as in claim 15 wherein concentration of the polymericquaternary ammonium compound in the composition is greater than 0.0007w/v % but less than 0.0015 w/v % of the pharmaceutical composition. 17.A composition as in claim 16 wherein the composition is disposed in aneye dropper.
 18. A composition as in claim 17 wherein concentration ofthe surfactant in the composition is less than 0.15 w/v %.
 19. Acomposition as in claim 18 wherein the composition satisfies Ph. Eur. A,Ph. Eur. B or both.
 20. A composition as in claim 19 wherein thecomposition has a pH of 6.4 to 7.2.
 21. A composition as in claim 20wherein the surfactant is non-ionic.